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The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling

Jin Li, Tamara Riedt, Steven Goossens UGent, Carmen Carrillo Garcia, Sabrina Szczepanski, Maria Brandes, Tim Pieters UGent, Linne Dobrosch, Ines Guetgemann, Natalie Farla UGent, et al. (2017) BLOOD. 129(4). p.460-472
abstract
Epithelial-to-mesenchymal-transition (EMT) is critical for normal embryogenesis and effective postnatal wound healing, but is also associated with cancer metastasis. SNAIL, ZEB, and TWIST families of transcription factors are key modulators of the EMT process, but their precise roles in adult hematopoietic development and homeostasis remain unclear. Here we report that genetic inactivation of Zeb2 results in increased frequency of stem and progenitor subpopulations within the bone marrow (BM) and spleen and that these changes accompany differentiation defects in multiple hematopoietic cell lineages. We found no evidence that Zeb2 is critical for hematopoietic stem cell self-renewal capacity. However, knocking out Zeb2 in the BM promoted a phenotype with several features that resemble human myeloproliferative disorders, such as BM fibrosis, splenomegaly, and extramedullary hematopoiesis. Global gene expression and intracellular signal transduction analysis revealed perturbations in specific cytokine and cytokine receptor-related signaling pathways following Zeb2 loss, especially the JAK-STAT and extracellular signal-regulated kinase pathways. Moreover, we detected some previously unknown mutations within the human Zeb2 gene (ZFX1B locus) from patients with myeloid disease. Collectively, our results demonstrate that Zeb2 controls adult hematopoietic differentiation and lineage fidelity through widespread modulation of dominant signaling pathways that may contribute to blood disorders.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
EPITHELIAL-MESENCHYMAL TRANSITION, SMAD-INTERACTING PROTEIN-1, STEM-CELL, HOMEOSTASIS, MIR-200 FAMILY, LYMPHOBLASTIC-LEUKEMIA, POSTMITOTIC, NEURONS, REPRESSORS ZEB1, SELF-RENEWAL, TGF-BETA, IN-VITRO
journal title
BLOOD
Blood
volume
129
issue
4
pages
460 - 472
Web of Science type
Article
Web of Science id
000396531400012
ISSN
0006-4971
DOI
10.1182/blood-2016-05-714659
language
English
UGent publication?
yes
classification
A1
additional info
the first three authors contributed equally to this manuscript
copyright statement
I have transferred the copyright for this publication to the publisher
id
8517350
handle
http://hdl.handle.net/1854/LU-8517350
date created
2017-04-07 14:50:57
date last changed
2017-07-13 14:24:06
@article{8517350,
  abstract     = {Epithelial-to-mesenchymal-transition (EMT) is critical for normal embryogenesis and effective postnatal wound healing, but is also associated with cancer metastasis. SNAIL, ZEB, and TWIST families of transcription factors are key modulators of the EMT process, but their precise roles in adult hematopoietic development and homeostasis remain unclear. Here we report that genetic inactivation of Zeb2 results in increased frequency of stem and progenitor subpopulations within the bone marrow (BM) and spleen and that these changes accompany differentiation defects in multiple hematopoietic cell lineages. We found no evidence that Zeb2 is critical for hematopoietic stem cell self-renewal capacity. However, knocking out Zeb2 in the BM promoted a phenotype with several features that resemble human myeloproliferative disorders, such as BM fibrosis, splenomegaly, and extramedullary hematopoiesis. Global gene expression and intracellular signal transduction analysis revealed perturbations in specific cytokine and cytokine receptor-related signaling pathways following Zeb2 loss, especially the JAK-STAT and extracellular signal-regulated kinase pathways. Moreover, we detected some previously unknown mutations within the human Zeb2 gene (ZFX1B locus) from patients with myeloid disease. Collectively, our results demonstrate that Zeb2 controls adult hematopoietic differentiation and lineage fidelity through widespread modulation of dominant signaling pathways that may contribute to blood disorders.},
  author       = {Li, Jin and Riedt, Tamara and Goossens, Steven and Garcia, Carmen Carrillo and Szczepanski, Sabrina and Brandes, Maria and Pieters, Tim and Dobrosch, Linne and Guetgemann, Ines and Farla, Natalie and Radaelli, Enrico and Hulpiau, Paco and Mallela, Nikhil and Froehlich, Holger and La Starza, Roberta and Matteucci, Caterina and Chen, Tong and Brossart, Peter and Mecucci, Cristina and Huylebroeck, Danny and Haigh, Jody J and Janzen, Viktor},
  issn         = {0006-4971},
  journal      = {BLOOD},
  keyword      = {EPITHELIAL-MESENCHYMAL TRANSITION,SMAD-INTERACTING PROTEIN-1,STEM-CELL,HOMEOSTASIS,MIR-200 FAMILY,LYMPHOBLASTIC-LEUKEMIA,POSTMITOTIC,NEURONS,REPRESSORS ZEB1,SELF-RENEWAL,TGF-BETA,IN-VITRO},
  language     = {eng},
  number       = {4},
  pages        = {460--472},
  title        = {The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling},
  url          = {http://dx.doi.org/10.1182/blood-2016-05-714659},
  volume       = {129},
  year         = {2017},
}

Chicago
Li, Jin, Tamara Riedt, Steven Goossens, Carmen Carrillo Garcia, Sabrina Szczepanski, Maria Brandes, Tim Pieters, et al. 2017. “The EMT Transcription Factor Zeb2 Controls Adult Murine Hematopoietic Differentiation by Regulating Cytokine Signaling.” Blood 129 (4): 460–472.
APA
Li, Jin, Riedt, T., Goossens, S., Garcia, C. C., Szczepanski, S., Brandes, M., Pieters, T., et al. (2017). The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling. BLOOD, 129(4), 460–472.
Vancouver
1.
Li J, Riedt T, Goossens S, Garcia CC, Szczepanski S, Brandes M, et al. The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling. BLOOD. 2017;129(4):460–72.
MLA
Li, Jin, Tamara Riedt, Steven Goossens, et al. “The EMT Transcription Factor Zeb2 Controls Adult Murine Hematopoietic Differentiation by Regulating Cytokine Signaling.” BLOOD 129.4 (2017): 460–472. Print.